Coordinate Regulation Research Articles

Coordinate transcriptional regulation of ErbB2/3 by C-terminal binding protein 2 signals sensitivity to ErbB2 inhibition in pancreatic adenocarcinoma

There is a critical need to identify new therapeutic vulnerabilities in pancreatic ductal adenocarcinoma (PDAC). Transcriptional co-regulators C-terminal binding proteins (CtBP) 1 and 2 are highly overexpressed in human PDAC, and CRISPR-based homozygous deletion of Ctbp2 in a mouse PDAC cell line (CKP) dramatically decreased tumor growth, reduced metastasis, and prolonged survival in orthotopic mouse allografts. Transcriptomic profiling of tumors derived from CKP vs. Ctbp2-deleted CKP cells (CKP/KO) revealed significant downregulation of the EGFR-superfamily receptor Erbb3, the heterodimeric signaling partner for both EGFR and ErbB2. Compared with CKP cells, CKP/KO cells also demonstrated reduced Erbb2 expression and did not activate downstream Akt signaling after stimulation of Erbb3 by its ligand neuregulin-1. ErbB3 expression in human PDAC cell lines was similarly dependent on CtBP2 and depletion of ErbB3 in a human PDAC cell line severely attenuated growth, demonstrating the critical role of ErbB3 signaling in maintaining PDAC cell growth. Sensitivity to the ErbB2-targeted tyrosine kinase inhibitor lapatinib, but not the EGFR-targeted agent erlotinib, varied in proportion to the level of ErbB3 expression in mouse and human PDAC cells, suggesting that an ErBb2 inhibitor can effectively leverage CtBP2-driven transcriptional activation of physiologic ErbB2/3 expression and signaling in PDAC cells for therapeutic benefit.

MIGGRI: A multi-instance graph neural network model for inferring gene regulatory networks for Drosophila from spatial expression images.

Recent breakthrough in spatial transcriptomics has brought great opportunities for exploring gene regulatory networks (GRNs) from a brand-new perspective. Especially, the local expression patterns and spatio-temporal regulation mechanisms captured by spatial expression images allow more delicate delineation of the interplay between transcript factors and their target genes. However, the complexity and size of spatial image collections pose significant challenges to GRN inference using image-based methods. Extracting regulatory information from expression images is difficult due to the lack of supervision and the multi-instance nature of the problem, where a gene often corresponds to multiple images captured from different views. While graph models, particularly graph neural networks, have emerged as a promising method for leveraging underlying structure information from known GRNs, incorporating expression images into graphs is not straightforward. To address these challenges, we propose a two-stage approach, MIGGRI, for capturing comprehensive regulatory patterns from image collections for each gene and known interactions. Our approach involves a multi-instance graph neural network (GNN) model for GRN inference, which first extracts gene regulatory features from spatial expression images via contrastive learning, and then feeds them to a multi-instance GNN for semi-supervised learning. We apply our approach to a large set of Drosophila embryonic spatial gene expression images. MIGGRI achieves outstanding performance in the inference of GRNs for early eye development and mesoderm development of Drosophila, and shows robustness in the scenarios of missing image information. Additionally, we perform interpretable analysis on image reconstruction and functional subgraphs that may reveal potential pathways or coordinate regulations. By leveraging the power of graph neural networks and the information contained in spatial expression images, our approach has the potential to advance our understanding of gene regulation in complex biological systems.

Multistakeholder platforms for integrated landscape governance: The case of Kalomo District, Zambia

Multistakeholder platforms (MSPs) that bring together a range of actors to collaboratively address land and natural resource governance issues are increasingly common in sub-Saharan Africa. However, the extent to which such platforms effectively harmonise complex social-ecological challenges and deliver improved outcomes is poorly understood. This study examines how MSPs across different scales of governance in Zambia have influenced and facilitated more integrated landscape governance. Based on literature review, policy document analysis and key informant interviews, we found that MSPs vary in form, function, influence and efficacity. Both formal and informal MSPs were found to enhance deliberative governance through the participation of key actors who contribute towards efforts to reconcile diverging and potentially conflicting interests. At the national level, MSPs benefit from broad actor presence and opportunities to lobby for policy and institutional change. Legally instituted MSPs at the district level provide a bridge between national policy development and local resource governance. Meanwhile, informal and formal local-level MSPs are strong in addressing resource conflicts and fostering community coordination and customary rules and regulations. However, local-level MSPs are less successful in influencing policy change due to weak linkages with formal governance institutions. These weak linkages between local and national governance levels have negative downward effects (i.e. poor policy performance and policies not taking root at the local level). We conclude that while MSPs offer the potential to improve stakeholder dialogue, deliberate feedback loops and enhanced linkages with other stakeholders at both district and national levels are needed to achieve more collaborative, equitable and effective landscape governance.

Reflection on Telework in Social Security Coordination

Telework has become prevalent during the COVID-19 pandemic, which has changed the way we look at work. However, the current EU rules for social security coordination were not designed to accommodate telework, with the lex loci laboris principle being understood in practical terms. During the pandemic, the European Commission initially suspended the coordination regulation rules to prevent sudden changes for workers, which caused unintended consequences and potential discrimination against intra-community migrants. To address these issues, options include changing the legal text of the coordination regulation, reinterpreting coordination rules, or concluding bilateral or multilateral agreements. Failure to take action could lead to continued discrimination by companies. In this regard, if no legislative action is taken, at least a common approach within the context of the Administrative Commission should be envisaged to ensure uniformity at the European level. The recent developments within the context of the Administrative Commission at least seem to go in that direction.

Coordination engineering regulating metal single-atom anchored on n-doped carbon as a bifunctional catalyst for H2O2 production via dual channels

Electrochemical synthesis of hydrogen peroxide (H2O2) via two-electron oxygen reduction reaction (2e- ORR) or two-electron water oxidation reaction (2e- WOR), parades great prospects in substituting traditional anthraquinone process. However, the low efficiency and selectivity hinders its practical utilization. Exploration of a bifunctional catalyst capable of simultaneously driving the 2e- WOR and 2e- ORR is crucial for thoroughly improving H2O2 conversion efficiency. Herein, by means of first principles calculation, the 2e- ORR and 2e- WOR activities of metal-nitrogen doped carbon (M−NC, M = Mn, Fe, Co, Ni, Ru, In, and Pt) are investigated. Combining the pyrrole nitrogen coordination regulation, the best sample (RuN(Po)4) is screened from forty single atom configurations, which exhibits ultra-low overpotentials (0.02 V/0.04 V) and excellent inhibition on 4e- ORR/WOR side reactions. In-depth study further verifies its low reaction energy barrier and high thermodynamic stability for H2O2 synthesis in two pathways. Our work is expected to provide useful understanding for designing highly-efficient bifunctional catalysts for H2O2 production.

The role of education models under the red sports culture in attention deficit disorder students

BackgroundAlthough physical education is considered to be beneficial for attention deficit disorder students in general, the therapeutic role of physical education models based on red sports culture optimization for this group has not been extensively studied. Therefore, it is important to further explore the physical education model optimized by red sports culture for the therapeutic effect of students with attention deficit disorder.Subjects and MethodsThe study first let a proportion of participants receive the physical education model intervention under red sports culture optimization. The intervention includes the following aspects, individualized exercise program selection, individual guidance and coaching, focus training, emotion regulation skills, etc. The intervention can be conducted through classroom teaching, group activities, individual instruction, and other forms. Control participants received the traditional physical education mode, and the data were analyzed using 3D-CAM during the experiment.ResultsThe analysis found that the participants had different degrees of improvement in their attentional control, motor coordination and emotional regulation after receiving the physical education model intervention under the red sports culture optimization. Meanwhile, the results showed that 84.3% of attention deficit disorder students improved their social skills.ConclusionsThis study provides guidance and reference for improving and optimizing the physical education model to better meet the needs of students with attention deficit disorder. The findings will provide practical application value to educators, medical professionals and parents to help them better support and promote the development and adaptability of students with attention deficit disorderAcknowledgementThe scientific research fund of Inner Mongolia University for nationalities, No. NMDYB20013.

Full-length transcriptome analysis revealed that 2,4-dichlorophenoxyacetic acid promoted in vitro bulblet initiation in lily by affecting carbohydrate metabolism and auxin signaling.

Bulblet initiation, including adventitious bud initiation and bulblet formation, is a crucial process for lily and other bulbous flowers that are commercially propagated by vegetative means. Here, by a hybrid strategy combining Pacific Biosciences (PacBio) full-length sequencing and Illumina RNA sequencing (RNA-seq), high-quality transcripts of L. brownii (Lb) and its variety, L. brownii var. giganteum (Lbg), during in vitro bulblet initiation were obtained. A total of 53,576 and 65,050 high-quality non-redundant full-length transcripts of Lbg and Lb were generated, respectively. Morphological observation showed that Lbg possessed a stronger capacity to generate bulblets in vitro than Lb, and 1 mg L-1 2,4-dichlorophenoxyacetic acid (2,4-D) significantly increased bulblet regeneration rate in two lilies. Screening of differentially expressed transcripts (DETs) between different stages and Mfuzz analysis showed 0 DAT to 1 DAT was the crucial stage with the most complex transcriptional change, with carbohydrate metabolism pathway was significantly enriched. In addition, 6,218 and 8,965 DETs were screened between the 2,4-D-treated group and the control group in Lbg and Lb, respectively. 2,4-D application had evident effects on the expression of genes involved in auxin signaling pathway, such as TIRs, ARFs, Aux/IAAs, GH3s and SAURs. Then, we compared the expression profiles of crucial genes of carbohydrate metabolism between different stages and different treatments. SUSs, SUTs, TPSs, AGPLs, GBSSs and SSs showed significant responses during bulblet initiation. The expression of CWINs, SUTs and SWEETs were significantly upregulated by 2,4-D in two lilies. In addition, 2,4-D increased the expression of starch degradation genes (AMYs and BAMs) and inhibited starch synthesis genes (AGPLs, GBSSs and SSs). SBEs were significantly upregulated in Lbg but not in Lb. Significant co-expression was showed between genes involved in carbohydrate metabolism and auxin signaling, together with transcription factors such as bHLHs, MYBs, ERFs and C3Hs. This study indicates the coordinate regulation of bulblet initiation by carbohydrate metabolism and auxin signaling, serving as a basis for further studies on the molecular mechanism of bulblet initiation in lily and other bulbous flowers.

The Location Choice and Survival of Polluting Firms under Environmental Regulation in Urban Agglomerations of China

There are few studies discussing the relationship between the increasing intensity of environmental regulation in the central cities of urban agglomerations, which is the main method used to solve the problem of regional environmental pollution, with the survival status of polluting firms in different spatial locations. In order to more clearly describe the evolution trend of the spatial distribution of polluting firms and coordinate inter-city environmental regulation policies in a more targeted manner, we examine the impact of polluting firms’ location choice on their survival under the central–periphery spatial structure in national-level urban agglomerations from 1998 to 2013 with the accelerated failure time (AFT) model and Cox proportional hazards (Cox PH) model and using matching data of the Chinese Industrial Enterprise Database and the Chinese Industrial Enterprise Pollution Emission Database. The results find that (1) under the influence of central cities’ environmental regulations, there is likely to be an inverted U-shaped relationship between the survival of polluting firms and their spatial distance from the central cities; (2) the inverted U-shaped relationship is the motivation of the interaction between environmental regulation and market potential, which means increases in the environmental regulation intensity in the central cities of the urban agglomeration will have a negative effect on the survival of polluting firms, and the central cities’ market potential will partially offset the negative impact; (3) the inverted U-shaped relationship is more significant for private firms, and it does not necessarily exist for new entrants. The above results help to provide important policy inspiration for promoting the joint prevention and control mechanism for pollution in urban agglomerations and coordinate the effects of environmental regulation and economic transformation policies between central and peripheral cities.

Local flux coordination and global gene expression regulation in metabolic modeling

Genome-scale metabolic networks (GSMs) are fundamental systems biology representations of a cell’s entire set of stoichiometrically balanced reactions. However, such static GSMs do not incorporate the functional organization of metabolic genes and their dynamic regulation (e.g., operons and regulons). Specifically, there are numerous topologically coupled local reactions through which fluxes are coordinated; the global growth state often dynamically regulates many gene expression of metabolic reactions via global transcription factor regulators. Here, we develop a GSM reconstruction method, Decrem, by integrating locally coupled reactions and global transcriptional regulation of metabolism by cell state. Decrem produces predictions of flux and growth rates, which are highly correlated with those experimentally measured in both wild-type and mutants of three model microorganisms Escherichia coli, Saccharomyces cerevisiae, and Bacillus subtilis under various conditions. More importantly, Decrem can also explain the observed growth rates by capturing the experimentally measured flux changes between wild-types and mutants. Overall, by identifying and incorporating locally organized and regulated functional modules into GSMs, Decrem achieves accurate predictions of phenotypes and has broad applications in bioengineering, synthetic biology, and microbial pathology.

Spin-State Modulation on Metal-Organic Frameworks for Electrocatalytic Oxygen Evolution.

Electrochemical oxygen evolution reaction (OER) kinetics are heavily correlated with hybridization of the transition metal d-orbital and oxygen intermediate p-orbital, which dictates the barriers of intermediate adsorption/desorption on the active sites of catalysts. Herein, a strategy is developed involving strain engineering and coordination regulation to enhance the hybridization of Ni 3d and O 2p orbitals, and the as-synthesized Ni-2,6-naphthalenedicarboxylic acid metal-organic framework (DD-Ni-NDA) nanosheets deliver a low OER overpotential of 260mV to reach 10mAcm-2 . By integrating an alkaline anion exchange membrane electrolyzer and Pt/C electrode, 200 and 500mAcm-2 current densities are reached with cell voltages of 1.6 and 2.1V, respectively. When loaded on a BiVO4 photoanode, the nanosheet enables highly active solar-driven water oxygen. Structural characterizations together with theoretical calculations reveal that the spin state of the centre Ni atoms is regulated by the tensile strain and unsaturated coordination defects in DD-Ni-NDA, and such spin regulation facilitates spin-dependent charge transfer of the OER. Molecular orbital hybridization analysis reveals the mechanism of OH* and OOH* adsorption energy regulation by changes in the DD-Ni-NDA spin state, which provides a deeper understanding of the electronic structure design of catalysts for the OER.

Coordinated expression of replication-dependent histone genes from multiple loci promotes histone homeostasis in Drosophila.

Production of large amounts of histone proteins during S phase is critical for proper chromatin formation and genome integrity. This process is achieved in part by the presence of multiple copies of replication dependent (RD) histone genes that occur in one or more clusters in metazoan genomes. In addition, RD histone gene clusters are associated with a specialized nuclear body, the histone locus body (HLB), which facilitates efficient transcription and 3' end-processing of RD histone mRNA. How all five RD histone genes within these clusters are coordinately regulated such that neither too few nor too many histones are produced, a process referred to as histone homeostasis, is not fully understood. Here, we explored the mechanisms of coordinate regulation between multiple RD histone loci in Drosophila melanogaster and Drosophila virilis. We provide evidence for functional competition between endogenous and ectopic transgenic histone arrays located at different chromosomal locations in D. melanogaster that helps maintain proper histone mRNA levels. Consistent with this model, in both species we found that individual histone gene arrays can independently assemble an HLB that results in active histone transcription. Our findings suggest a role for HLB assembly in coordinating RD histone gene expression to maintain histone homeostasis.

Tuning the Pt-N coordination in Pt/MOFs nanosheets under N2 plasma for enhanced oxygen reduction reaction

Regulation of the local coordination of metal sites can tune the electronic structure of catalysts, thereby improving electrocatalytic activity and reaction selectivity. This study proposes a strategy for designing highly active catalysts by regulating Pt-N coordination through N2 plasma treatment. Zn-BDC (1,4-benzenedicarboxylic acid) nanosheets embedded with Pt nanoparticles (Pt/Zn-BDC) were successfully fabricated. Subsequently, radio frequency (RF) discharge N2 plasma was applied to tune the Pt sites of Pt/Zn-BDC at room temperature. The plasma-treated Pt/Zn-BDC showed enhanced catalytic activity for the oxygen reduction reaction (ORR) with a high half-wave potential (0.835 V), superior to those of pristine Pt/Zn-BDC and 20 wt% Pt/C. Notably, rechargeable Zn-air batteries based on plasma-treated catalysts were demonstrated to exhibit high efficiency and stability. The enhanced catalytic performance originated from the optimized coordination environment and electronic structure of the Pt sites under N2 plasma treatment. This study provides a facile, green method of regulating promising ORR electrocatalysts via low-temperature plasma treatment.

Current Benefits of ASCE 75 and its Potential to Affect Digital As-Built Initiatives at State Departments of Transportation

For the proactive documentation of utility infrastructure at the time of its installation, the American Society of Civil Engineering (ASCE) is finalizing their ASCE 75 “Standard Guideline for Recording and Exchanging Utility Infrastructure Data.” ASCE 75 provides guidance for collecting sufficient geospatial and attribute data of utilities to facilitate the development of precise 3D digital twins. Some state departments of transportation (DOTs) in the U.S. have already adopted draft versions of ASCE 75 and are attempting to use it to assist their efforts to standardize and expedite their utility accommodation, permitting, and highway project coordination regulations and procedures. In alignment with these efforts, the Federal Highway Administration’s “Every Day Counts Round Six” initiative illustrates the importance of digital as-built (DAB) records by stating that their implementation can enhance safety, quality, and cost savings. However, there is no standard practice for the general construction DABs. Therefore, this study illustrates the benefits of implementing the ASCE 75 utility as-built standard and its potential impact on DABs for general construction. This study used a research methodology comprised of interviewing state DOTs, and a comprehensive literature assessment. The benefits of implementing ASCE 75 include improved data exchange methods among the project stakeholders and the collection and exchange of data about subsurface and above-ground utilities’ location and other attributes. Moreover, ASCE 75 provides a framework for all infrastructure projects. Also, the study highlights how ASCE 75 is adopted across the state DOTs and how it presents a path forward beyond just developing a utility as-built standard.

SIX1 and EWS/FLI1 co-regulate an anti-metastatic gene network in Ewing Sarcoma

Ewing sarcoma (ES), which is characterized by the presence of oncogenic fusion proteins such as EWS/FLI1, is an aggressive pediatric malignancy with a high rate of early dissemination and poor outcome after distant spread. Here we demonstrate that the SIX1 homeoprotein, which enhances metastasis in most tumor types, suppresses ES metastasis by co-regulating EWS/FLI1 target genes. Like EWS/FLI1, SIX1 promotes cell growth/transformation, yet dramatically inhibits migration and invasion, as well as metastasis in vivo. We show that EWS/FLI1 promotes SIX1 protein expression, and that the two proteins share genome-wide binding profiles and transcriptional regulatory targets, including many metastasis-associated genes such as integrins, which they co-regulate. We further show that SIX1 downregulation of integrins is critical to its ability to inhibit invasion, a key characteristic of metastatic cells. These data demonstrate an unexpected anti-metastatic function for SIX1, through coordinate gene regulation with the key oncoprotein in ES, EWS/FLI1.

Long wavelength-sensing cones of zebrafish retina exhibit multiple layers of transcriptional heterogeneity.

Understanding how photoreceptor genes are regulated is important for investigating retinal development and disease. While much is known about gene regulation in cones, the mechanism by which tandemly-replicated opsins, such as human long wavelength-sensitive and middle wavelength-sensitive opsins, are differentially regulated remains elusive. In this study, we aimed to further our understanding of transcriptional heterogeneity in cones that express tandemly-replicated opsins and the regulation of such differential expression using zebrafish, which express the tandemly-replicated opsins lws1 and lws2. We performed bulk and single cell RNA-Seq of LWS1 and LWS2 cones, evaluated expression patterns of selected genes of interest using multiplex fluorescence in situ hybridization, and used exogenous thyroid hormone (TH) treatments to test selected genes for potential control by thyroid hormone: a potent, endogenous regulator of lws1 and lws2 expression. Our studies indicate that additional transcriptional differences beyond opsin expression exist between LWS1 and LWS2 cones. Bulk RNA-Seq results showed 95 transcripts enriched in LWS1 cones and 186 transcripts enriched in LWS2 cones (FC > 2, FDR < 0.05). In situ hybridization results also reveal underlying heterogeneity within the lws1- and lws2-expressing populations. This heterogeneity is evident in cones of mature zebrafish, and further heterogeneity is revealed in transcriptional responses to TH treatments. We found some evidence of coordinate regulation of lws opsins and other genes by exogenous TH in LWS1 vs. LWS2 cones, as well as evidence of gene regulation not mediated by TH. The transcriptional differences between LWS1 and LWS2 cones are likely controlled by multiple signals, including TH.

Structural insights into regulation of CNNM-TRPM7 divalent cation uptake by the small GTPase ARL15.

Cystathionine-β-synthase (CBS)-pair domain divalent metal cation transport mediators (CNNMs) are an evolutionarily conserved family of magnesium transporters. They promote efflux of Mg2+ ions on their own and influx of divalent cations when expressed with the transient receptor potential ion channel subfamily M member 7 (TRPM7). Recently, ADP-ribosylation factor-like GTPase 15 (ARL15) has been identified as CNNM-binding partner and an inhibitor of divalent cation influx by TRPM7. Here, we characterize ARL15 as a GTP and CNNM-binding protein and demonstrate that ARL15 also inhibits CNNM2 Mg2+ efflux. The crystal structure of a complex between ARL15 and CNNM2 CBS-pair domain reveals the molecular basis for binding and allowed the identification of mutations that specifically block binding. A binding deficient ARL15 mutant, R95A, failed to inhibit CNNM and TRPM7 transport of Mg2+ and Zn2+ ions. Structural analysis and binding experiments with phosphatase of regenerating liver 2 (PRL2 or PTP4A2) showed that ARL15 and PRLs compete for binding CNNM to coordinate regulation of ion transport by CNNM and TRPM7.

The binding nature of posting PDA1 issued under EU social security Coordination Regulations and the possible role of national courts

The EU social security Coordination Regulations envisage a special conflict rule that, under strict conditions, allows posted workers to maintain temporarily the social security insurance of the home Member State. The Portable Document A1 (PDA1), the proof of insurance, is a binding document for the institutions and courts of the host Member State that can only be invalidated or withdrawn by the institutions that issued it or by the corresponding national courts. The case-law of the European Court of Justice has clarified that under certain very specific circumstances a fraudulent foreign PDA1 can be disregarded by a Court, but never invalidated. Communication and collaboration between institutions of the issuing and receiving Member States and the judicial procedures for challenging a foreign PDA1 may need to be enhanced and improved, but the current rules of play respond to the logic of the Coordination Regulations, to sincere cooperation, to legal certainty, and to the uniqueness of the applicable law and the competent jurisdiction. The scarce available data shows that only a few of the three million PDA1s issued each year are being challenged. Given that the main role of the EU legislation is to protect workers, it does not seem logical to change the social security framework of posting, although it can be improved. Mutual trust must be restored.

Examining the Threshold Effect of Environmental Regulation: The Impact of Agricultural Product Trade Openness on Agricultural Carbon Emissions

Agricultural product trade openness is a crucial factor impacting agricultural carbon emissions. This study analyzes the relationship between trade openness and carbon emissions in China. Using panel data from 2002 to 2020 for 31 provinces, a threshold panel model is employed to examine the non-linear relationship from an environmental regulation perspective. The findings reveal a significant single-threshold effect of environmental regulation. When environmental regulation intensity is low, trade openness is positively associated with agricultural carbon emissions. However, when environmental regulation intensity is high, trade openness significantly reduces carbon emissions. Regional regression analysis indicates that this single-threshold effect holds true in major grain-producing, grain-selling, and grain- producing- selling balance areas, although regional differences exist. This study emphasizes the need to coordinate environmental regulations and trade policies, strengthen environmental control, and leverage the threshold effect of environmental regulation in reducing carbon emissions through agricultural product trade openness.

Reduced histone gene copy number disrupts Drosophila Polycomb function.

The chromatin of animal cells contains two types of histones: canonical histones that are expressed during S phase of the cell cycle to package the newly replicated genome, and variant histones with specialized functions that are expressed throughout the cell cycle and in non-proliferating cells. Determining whether and how canonical and variant histones cooperate to regulate genome function is integral to understanding how chromatin-based processes affect normal and pathological development. Here, we demonstrate that variant histone H3.3 is essential for Drosophila development only when canonical histone gene copy number is reduced, suggesting that coordination between canonical H3.2 and variant H3.3 expression is necessary to provide sufficient H3 protein for normal genome function. To identify genes that depend upon, or are involved in, this coordinate regulation we screened for heterozygous chromosome 3 deficiencies that impair development of flies bearing reduced H3.2 and H3.3 gene copy number. We identified two regions of chromosome 3 that conferred this phenotype, one of which contains the Polycomb gene, which is necessary for establishing domains of facultative chromatin that repress master regulator genes during development. We further found that reduction in Polycomb dosage decreases viability of animals with no H3.3 gene copies. Moreover, heterozygous Polycomb mutations result in de-repression of the Polycomb target gene Ubx and cause ectopic sex combs when either canonical or variant H3 gene copy number is reduced. We conclude that Polycomb-mediated facultative heterochromatin function is compromised when canonical and variant H3 gene copy number falls below a critical threshold.

Surviving and Adapting to Stress: Translational Control and the Integrated Stress Response.

Significance: Organisms adapt to changing environments by engaging cellular stress response pathways that serve to restore proteostasis and enhance survival. A primary adaptive mechanism is the integrated stress response (ISR), which features phosphorylation of the α subunit of eukaryotic translation initiation factor 2 (eIF2). Four eIF2α kinases respond to different stresses, enabling cells to rapidly control translation to optimize management of resources and reprogram gene expression for stress adaptation. Phosphorylation of eIF2 blocks its guanine nucleotide exchange factor, eIF2B, thus lowering the levels of eIF2 bound to GTP that is required to deliver initiator transfer RNA (tRNA) to ribosomes. While bulk messenger RNA (mRNA) translation can be sharply lowered by heightened phosphorylation of eIF2α, there are other gene transcripts whose translation is unchanged or preferentially translated. Among the preferentially translated genes is ATF4, which directs transcription of adaptive genes in the ISR. Recent Advances and Critical Issues: This review focuses on how eIF2α kinases function as first responders of stress, the mechanisms by which eIF2α phosphorylation and other stress signals regulate the exchange activity of eIF2B, and the processes by which the ISR triggers differential mRNA translation. To illustrate the synergy between stress pathways, we describe the mechanisms and functional significance of communication between the ISR and another key regulator of translation, mammalian/mechanistic target of rapamycin complex 1 (mTORC1), during acute and chronic amino acid insufficiency. Finally, we discuss the pathological conditions that stem from aberrant regulation of the ISR, as well as therapeutic strategies targeting the ISR to alleviate disease. Future Directions: Important topics for future ISR research are strategies for modulating this stress pathway in disease conditions and drug development, molecular processes for differential translation and the coordinate regulation of GCN2 and other stress pathways during physiological and pathological conditions. Antioxid. Redox Signal. 39, 351-373.